In preliminary research, lung examination by 7.6 MHz diagnostic ultrasound (DUS) showed the rapid development comet-tail artifacts across the bright lung surface image. This progressing artifact was indicative of ongoing induction of pulmonary hemorrhage (PH), which was validated by observation of PH in the lung. A threshold was located at a low Mechanical Index of ~0.44, which is less than one quarter of the DUS upper limit in the United States. This troubling finding overturns present DUS safety assumptions and implies that patients may be at risk of lung injury. Pulsed-ultrasound induced PH was discovered more than 20 yr. ago, but the mechanism remains uncertain. Authoritative reviews in 2000 and 2008 recognized a potential for diagnostic ultrasound (DUS) induced PH (DUS-PH), but no useful safety strategy has been devised. At that time, only accidental lung exposure was expected, which seemed unlikely to cause PH. Unfortunately, this appearance of safety was ephemeral. New methods of DUS lung examination are now rapidly becoming routine in critical care medicine and other clinical settings, which benefits physician effectiveness and patient care. However, as pulmonary ultrasound becomes routine worldwide, many patients will receive deliberate lung exposure and suffer a risk of PH. A solution for this explosive safety issue is urgently needed. From the biophysical perspective, lung is a tissue dominated by gas, which must interact strongly with DUS. The central hypothesis is that DUS-PH starts from the direct impingement of ultrasound pulses on the blood-air barrier of pulmonary capillaries with hemorrhage resulting from capillary stress. This leads to progressive stress in alveolar septa leading to the contusion-like lung injury. Certain patient conditions having more vulnerable alveoli due to hypertension or edema may be particularly susceptible DUS-PH. The objective of this project is to gain a detailed understanding of DUS-PH and to correct the deficiency in safety guidance for pulmonary ultrasound. Our strategy has three specific aims: First, the relative susceptibility of the lung to DUS-PH will be investigated, using novel methods including image feedback, for different DUS modes and frequencies and for common patient conditions often diagnosed by pulmonary ultrasound. Second, mechanisms of DUS-PH will be identified by using intravital microscopy to characterize the initiation and progression of PH, which will allow physical modeling of the phenomena. Finally, a dosimetric algorithm for potential human DUS-PH will be developed and tested using a swine model of human DUS lung examination. The outcomes expected from achieving these aims are an understanding of lung susceptibility in different patients, a characterization of the biophysical processes leading to DUS-PH, and a human safety strategy suitable for sonographer education and guidance. These achievements will raise awareness of DUS-PH and assure patient safety while retaining the ability to acquire optimal DUS images. The overall impact of this project will be the initiation of new safety concepts for pulmonary ultrasound and the proactive solution of this emergent public health problem.